1. Field of the Invention
This invention relates to new ether and/or amide derivatives, which are useful for the treatment of diabetes and a pharmaceutical containing these compounds as active ingredients.
2. Current Technology
Biguanide and sulfonyl urea derivatives have been used as anti-diabetics so far. But these compounds have some drawbacks. For instance, biguanide compounds cause diabetic acidosis and sulfonyl urea compounds often cause hypoglycemia and it is required to be careful when taking these drugs.
Recently, thiazolidine-2,4-dione derivatives are reported to have blood glucose lowering activities. For example, Troglitazone (T. Yoshioka et al., J. Med. Chem. 1989, 32,421), Pioglitazone (H. Ikeda et al., J. Med. Chem. 1992, 35,2617) or Rosiglitazone (B. C. C. Cantello et al., J.Med. Chem. 1994, 37,3977) are mentioned as Thiazolidine-2,4dione derivatives and Troglitazone is applied for clinical use. However, these thiazolidine-2,4-dione compounds are reported to cause liver toxicity (R. Perfetti et al., Diabetes/Metabolism Review 1998,14(3),207) and further, side effects to troglitazone treatment have been reported. They include cardiomegaly and hepatic malfunction such as increase of amino trasferase (ATL), and lactic dehydrogenase (LDH) (R. R. Henry, Endocrinol.Metab,Clin,North AM. 1997,26,553).
To alleviate the side effect of thiazolidine-2,4-dione derivatives, several non-thiazolidine-2,4-diones are reported such as oxazoline-2,4-diones (R. L. Dow et al., J.Med.Chem. 1991,34,1538), 1-oxo-2,4-diazoline-3,5 dione (S. W. Goldstein et al., J.Med.Chem. 1993,36,2238), xcex1-amino carboxylic acid (R. A. DeFronzo, Diabetes, 1988,37,677), and Dicarboxylic acid ester (H. Shinkai et al., J.Med.Chem. 1998,41,1927).
The present invention concerns ether and amide compounds which enhance insulin action and show hypoglycemic activity with low toxicities and a pharmaceutical composition containing these compounds as active ingredients.
After extensive research to make an anti-diabetic drug, the inventors found that new compounds, as shown by general formula (I), have potent anti-diabetic activities and fulfilled this invention.
Namely, the invention is the compounds as shown in general formula (I) and its pharmaceutically acceptable salts and a composition containing these compounds as active ingredients.
R1xe2x80x94Axe2x80x94R2xe2x80x83xe2x80x83(I)
wherein 
(with the provisos that (i) when A is xe2x80x94Oxe2x80x94, then n is 2 or 3 (ii) when 
then
n is 1 or 2. R3 is OHxe2x80x94, CH3SO2NHxe2x80x94, CF3SO2NHxe2x80x94, CH3SO2NHCH2xe2x80x94, CF3SO2NHCH2xe2x80x94, HOOCxe2x80x94, CH3OOCxe2x80x94, 
xe2x80x83HOOCxe2x80x94CH2SO2NHxe2x80x94, CF3xe2x80x94CH2SO2NHxe2x80x94, 
R8xe2x80x94NHSO2xe2x80x94,
R8xe2x80x94NHSO2xe2x80x94CH2xe2x80x94, HOOCxe2x80x94CH2xe2x80x94Oxe2x80x94, HSO3Nxe2x95x90CHxe2x80x94, or R9xe2x80x94SO2NHCOxe2x80x94;
R4 is H, OH, O-alkyl or Oxe2x80x94CH2OCH3;
R5 is H, halogen atom, xe2x80x94CH2COOH or OH;
R6 and R7 are hydrogen, t-butyl or pyrolidyl;
R8 is hydrogen or lower alkyl;
R9 is alkyl or thienyl;
R10 is lower alkyl)
70 compounds are exemplified as follows, but the invention is not limited to these compounds. Further the preparation of the compounds 1-70 are exemplified in each experimental sections. 
Typical preparations of the compounds of general formula (I) according to the invention are shown.
(I) The preparation of a compound of general formula (I) in which
A is xe2x80x94Oxe2x80x94; 
(wherein: R5, R6, and R7 have the above-mentioned meanings; n=2)
(a) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94 and R4 is H.
The compounds can be obtained by means of the following reaction diagram: Asparatic acid xcex2-methyl ester (2) (J.Arg.Chem.Soc.Japan, 1951-1952,25,129): (C.A.47,6065i or R. L. Prestige et al., J.Org.Chem. 1975,40,3287) as a starting material is converted to compound (3) by the known method (B. Helvin et al.,J.Med.Chem. 1992,35.1853) and compound (3) is tosylated or mesylated to obtain compound (4). The coupling reaction of compound (4) with nitrophenol yields compound (5) and then compound (5) is reduced with H2xe2x80x94Pd/C to obtain compound (6) and compound (6) is subjected to reaction with sulfonyl chloride (7) or sulfonic acid anhydride (8) to obtain the compound of general formula (I). 
(b) In case of 
in which R3 is HOOCCH2SO2NHxe2x80x94 and R4 is H.
The compounds can be obtained by mean of the following reaction diagram:
The reaction of compound (6) and EtOOC.CH2SO2Cl as a sulfonyl chloride, namely CH3OOCH2SO3Cl (9), yields the ester (11) and then compound (11) is hydrolyzed to obtain the compound of general formula (I).
The above mentioned compound (9) is obtained by the chlorination of sulfoacetic acid (HOOCCH2SO3H(10)) with SOCl2 and then reacted with alcohol (R. L. Hinman et al. (J.Am.Chem. Soc. 1959,81,5655), (H. T. Lee et al.,Bioorg.Med.Chem.Lett.1998,8,289) 
(c) In case of 
in which R3is HOOCxe2x80x94CONHxe2x80x94 and R4 is H.
The compound can be obtained by means of the following reaction diagram:
The reaction of compound (6) and methyloxalate yields compound (12) and compound (12) is hydrolyzed to obtain the compound of general formula (I). Further compound (12) is N-alkylated with alkylhalide and then subjected to hydrolysis to obtain the compound of general formula (I). 
(d) In case of 
in which R3 is CH3SO2NHCH2xe2x80x94, CF3SO2NHCH2xe2x80x94and HOOCxe2x80x94CONHxe2x80x94, and R4 is H.
The compound can be obtained by means of the following reaction diagram:
Compound (4) is reacted with p-hydroxy benzaldehyde to obtain compound (13) and compound (13) is subjected to reductive amination using benzylamine and sodium borohydride to obtain compound (14).
After debenzylation of compound (14) in H2xe2x80x94Pd/C, compound (15) is obtained. Compound (15) is reacted with sulfonyl chloride, sulfonic acid anhydride, EtOOC.CH2SO2Cl or methyloxalate as the same manner as in case of compound (6) and compound (12), then the compound of general formula (I) is obtained. 
(e) In case of 
in which R3 is HOOCxe2x80x94 or CH3OOCxe2x80x94 and R4 is xe2x80x94OH or xe2x80x94O-alkyl.
As shown in the following reaction diagram,
compound (32) and compound (3) is subjected to the MITSUNOBU reaction to obtain the compound (33) which is the compound of general formula (I). 
Further, compound (33) can be converted to compound (34) and compound (36) as shown in the following diagram. 
(f) In case of 
in which R3 is NH2SO3xe2x80x94 or alkyl-NHS2xe2x80x94 and R4 is xe2x80x94OH.
As shown in the following reaction diagram,
according to the literature method (J.Med.Chem.1997,20,1235), compound (51) and (52) are obtained from resorcin dimethyl ether (50). 
Further, obtained compounds (51) and (52) are reacted with compound (4) to obtain general formula (I) as follows. 
(g) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2 NHxe2x80x94.
As shown in the following reaction diagram,
compound (53) is subjected to the MITSUNOBU reaction to obtain compound (54) and reduction of compound (54) yields compound (55). Compound (55) is converted to compound (56) according to the method of the preparation of compound (42) from compound (39). 
(h) In case of 
in which R3 is xe2x80x94COOH.
As shown in the following reaction diagram,
compound (57) is reacted with compound (4) and obtain the ether compound (58) and the resulting compound (58) is hydrolyzed to obtain compound (59) which is the compound of general formula (I). 
(i) In case of 
in which R3 is MeOOCCH2xe2x80x94, and R4 is xe2x80x94O-alkyl.
As shown in the following reaction diagram,
compound (61), which is obtained from compound (60), is reacted with compound (4) to obtain the compound of general formula (I). 
(j) In case of 
in which R3 is NH2SO2CH2xe2x80x94 or alkyl-NHS02CH2xe2x80x94 and R4 is OH or xe2x80x94O-alkyl.
As shown in the following reaction diagram,
after reduction of compound (62), the obtained compound (63) is reacted with Na2SO3 to obtain compound (64) according to the reported method (J.C.S.Chem.Comom.,1989,521). Then compound (64) is chlorinated with POCl3 and treated with aqueous NH3 to obtain the amide compound (65). After debenzylation of compound (65), compound (66) is obtained. Compound (66) is reacted with compound (4) to yield the compound of general formula (I). 
(II) The preparation of a compound of general formula (I) in which
A is xe2x80x94Oxe2x80x94; 
(wherein: R5, R6, and R7 have the above mentioned meaning; n=3)
(a) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94, and R4 is H.
As shown in the following reaction diagram,
glutamic acid xcex3-methyl ester (16) is used in stead of aspartic acid xcex2-methyl ester (2). Compound (17) is obtained from compound (16) by the same method as compound (3) is obtained from compound (2).
After compound (17) is halogenated, tosylated or mesylated, obtained compound (18) is coupled with nitrophenol and the resulting compound (19) is hydrogenated to obtain compound (20). The obtained compound (20) is reacted with one of sulfonyl chlorides, sulfonic acid anhydrides, EtOOC.CH2SO2Cl or methyloxalate to obtain the compound of general formula (I). 
(II) The preparation of a compound of general formula (I) in which
A is xe2x80x94Oxe2x80x94; 
(a) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94, and R4 is H.
As shown in the following reaction diagram,
after the reaction of 2-methyl 5-ethylpyridine (21) and formaldehyde using the reported method (Japanese Patent Publication,1981-65870), compound (22) is obtained. After compound (22) is halogenated, tosylated or mesylated, obtained compound (23) is coupled with nitrophenol and the resulting compound (24) is hydrogenated to obtain compound (25), by the same method as compound (4) is obtained from compound (3).
The obtained compound (25) is reacted with several sulfonylchlorides (7), sulfonic acid anhydrides (8), EtOOC.CH2SO2Cl or methyloxalate to obtain the compound of general formula (I). 
(b) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94, and R4 is xe2x80x94OH or xe2x80x94O-alkyl.
As shown in the following reaction diagram,
compound (37) is reacted with HOxe2x80x94R2 to obtain compound (38) and compound (38) is hydrogenated to compound (39), or compound (38) is alkylated to compound (40) and reduction of compound (40) yields compound (41). The compound (39) or (41) is reacted with RSO2Cl to obtain compound (42) or compound (43). 
Compound (37) in the diagram can be obtained from resorcin as follow. 
And compound (42) and (43) can be obtained by using the reported method of coupling reaction of fluorobenzene and alcohol (Bioorg.Med.Chem.Lett.,1994,4 (10),1181). Namely, 2-OMOM (methoxy methyl)-4-fluoro nitrobenzene (45) is reacted with HOxe2x80x94R2 to give compound (46) and resulting compound (46) is reduced to obtain compound (47).
Compound (47) is reacted with RSO2Cl to obtain compound (48) and after deprotection of MOM-group in compound (48), compound (42) is obtained.
Instead of compound (45), compound (49) is also converted to compound (41), and compound (43) is obtained from compound (41) by the same method as compound (48) is obtained from compound (46).
The process is shown in the following reaction diagram. 
(IV) The preparation of a compound of general formula (I) in which
A is xe2x80x94Oxe2x80x94; 
(a) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94, and R4 is xe2x80x94H.
As shown in the following reaction diagram,
compound (28), obtained from 2-chloropyridine (26) or 2-methyl amino pyridine (27), is tosylated or mesylated to obtain compound (29). Compound (29) is subjected to coupling reaction with nitro phenol and obtained compound (30) using the same manner to obtain compound (3). Resulting compound (30) is reduced to obtain compound (31) and compound (31) is reacted with sulfonyl chlorides (7), sulfonic acid anhydrides (8), EtOOC.CH2SO2Cl and methyloxalate to obtain the compound of general formula (I). 
(V) The preparation of a compound of general formula (I) in which
A is xe2x80x94NHxe2x80x94COxe2x80x94
(a) In case of 
in which R3 is CH3SO2NHxe2x80x94 or CF3SO2NHxe2x80x94, and R4 is xe2x80x94H.
As shown in the following reaction diagram,
compound (67), intermediate for compound (3), is obtained according to the reported method (J.Med.Chem.1999,35,1853) and compound (67) is hydrolyzed to obtain compound (68). After chlorination of compound (68), obtained chloride is reacted with p-nitroaniline to obtain compound (69). 
Then compound (69) is hydrogenated to obtain compound (70) according to the same method used to prepare compound (5). Compound (70) is reacted with sulfonyl chlorides (7), sulfonic acid anhydrides (8), EtOOC.CH2SO2Cl and methyloxalate to obtain the compound of general formula (I). 
(b) In case of 
in which R3 is R9SO2NHCOxe2x80x94 (R9=alkyl or thienyl), and R4 is H.
As shown in the following reaction diagram,
carboxylic acid of compound (71) is reacted with CDI (Carbonyl Diimidazole) and then subjected to react with sulfamine of compound (72) in the presence of DBU (1,8-Diazabicyclo[5,4,0]undeca-7-ene) and obtain the compound of general formula (I). (Bioorg.Med.Chem. Lett.1995,1155) 
As pharmaceutical acceptable salts of a compound of general formula (I), sodium salt, potassium salt and inorganic base are mentioned.
In case of R1 containing pyridine base, salts of inorganic and organic acids are mentioned. As the salt of inorganic acid, hydrochloride and sulfate are mentioned. As the salt of organic acid, acetate succinate and fumarate are mentioned.
A compound of general formula (I) can be used itself or formulated to pharmaceutical product such as powder, granule, tablet and capsule by known pharmaceutical technology.
Hypoglycemic Activity in Mice
Test compounds were suspended in 0.5% Methyl cellulose solution and administered (p.o.) to db/db mice (obtained from Nihon Clea) at a range of 3-30 mg/kg once a day for four consecutive days. Troglitazone (300 mg/kg) was also administrated for control. The results are shown in Table 1.
The compound number corresponds to the experimental number.